IL-6 trans-signalling (IL-6TS) is emerging as a pathogenic mechanism in chronic respiratory diseases, however the drivers of IL-6TS in the airways and the phenotypic characteristic of patients with increased IL-6TS pathway activation remain poorly understood.Our aim was to identify and characterize COPD patients with increased airway IL-6TS and to elucidate the biological drivers of IL-6TS pathway activation.We used an IL-6TS-specific sputum biomarker profile (sIL-6R, IL-6, IL-1β, IL-8, MIP-1β) to stratify sputum data from patients with COPD (n=74; BEAT-COPD) by hierarchical clustering. The IL-6TS signature was related to clinical characteristics and sputum microbiome profiles. The induction of neutrophil extracellular trap formation (NETosis) and IL-6TS by Haemophilus influenzae were studied in human neutrophils.Hierarchical clustering revealed an IL-6TS-high subset (n=24) of COPD patients, which shared phenotypic traits with an IL-6TS-high subset previously identified in asthma. The subset was characterized by increased sputum cell counts (p=0.0001), persistent sputum neutrophilia (p=0.0004), reduced quality of life (CRQ total score; p=0.008), and increased levels of pro-inflammatory mediators and MMPs in sputum. IL-6TS-high COPD patients showed an increase in Proteobacteria, with Haemophilus as the dominating genus. NETosis induced by H. influenzae was identified as a potential mechanism for increased soluble IL-6 receptor (sIL-6R) levels. This was supported by a significant positive correlation between sIL-6R and NETosis markers in bronchoalveolar lavage fluid from COPD patients.IL-6TS pathway activation due to chronic colonization with Haemophilus may be an important disease driver in a subset of COPD patients.
Sofia Winslow, Lina Odqvist, Sarah Diver, Rebecca Riise, Suado Abdillahi, Cecilia Wingren, Helena Lindmark, Annika Wellner, Sofia Lundin, Linda Yrlid, Elisabeth Ax, Ratko Djukanovic, Sriram Sridhar, Andrew Higham, Dave Singh, Thomas Southworth, Christopher E Brightling, Henric K Olsson, Zala Jevnikar